The Prognostic Importance of ctDNA in Rectal Cancer: A Critical Reappraisal
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
Quality Appraisal
3. Results
3.1. Quality Appraisal
3.2. Study Characteristics
3.3. Measurement of ctDNA
3.4. Outcome
3.4.1. ctDNA at Baseline
3.4.2. ctDNA after CRT
3.4.3. ctDNA after Surgery
4. Discussion
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Database | Search Term 1 | Search Term 2 |
---|---|---|
Pubmed | rectal neoplasms (Mesh) | dna methylation (MeSH Terms) |
rectal cancer (Title/Abstract) | “methylated dna” (Title/Abstract) ctDNA (Title/Abstract) | |
“circulating tumour dna”(Title/Abstract) | ||
“circulating tumor dna” (Title/Abstract) cfdna (Title/Abstract) | ||
“cell free dna” (Title/Abstract) | ||
“liquid biopsy” | ||
Embase | rectal cancer (keyword) | ctdna (keyword) |
rectum cancer (subject heading) | circulating tumo?r dna (keyword) | |
rectal malignancy (keyword) | circulating tumor DNA (subject heading) | |
“cell free dna” (keyword) | ||
cfdna (keyword) | ||
“methylated dna” (keyword) | ||
DNA methylation (subject heading) | ||
liquid biopsy (subject heading) | ||
liquid biops* (keyword) | ||
Scopus | search within title, abstract | “circulating tumour dna” |
or keyword | ctdna | |
rectal cancer | “cell free dna” | |
rectal neoplasms | cfdna | |
“dna methylation” | ||
“methylated dna” | ||
“liquid biopsy |
Study | No. | Patient Characteristics | ctDNA Measurements | Assay | Median Follow-Up | Main Findings |
---|---|---|---|---|---|---|
Appelt et al. (2019) | 146 | age 64 64% male 88% stage III | Baseline | ddPCR | 10.6 years (range 9.2–11.5) for OS | There was no association between meth-ctDNA status at baseline and complete (OR 0.64 95% CI 0.11–2.49, p = 0.76) or major tumor regression (OR 1.13 95% CI 0.4–3.54, p = 1.0). Patients with meth ctDNA had worse OS at 5 years (47% vs. 69% p = 0.02). Regression analysis demonstrated that meth-ctDNA is a strong independent prognostic factor for OS (HR 2.08 95% CI 1.23–1.51) and freedom from distant metastases (HR 2.20 95% CI 1.19–4.07). |
Sclafani et al. (2017) | 97 | age 62.1 60% male 69% stage III | Baseline | ddPCR | NA | There was no difference in CR rate (15.4% vs. 10% OR 1.63 95% CI 0.3–8.96, p = 0.57), PFS (HR 0.70 95% CI 0.29–1.7, p = 0.43) or OS (HR 0.78 95% CI 0.31–1.96, p = 0.60) between ctDNA-positive and ctDNA-negative patients. |
Vidal et al. (2021) | 62 | age 62 64.5% male 100% stage III | Baseline and before surgery | NGS | 38 months (range 2.3–51.5) for DFS and OS | No association between ctDNA at baseline and ypCR (p = 0.134). Detectable ctDNA at baseline was not associated with DFS (p = 0.59) or OS (p = 0.38). Patients with detectable ctDNA prior to surgery had increased risk of recurrence (HR 4.0 95% CI 1.0–16.2, p = 0.033) and a markedly reduced survival (HR 23 95% CI 2.4–212, p < 0.0001). DFS at 3 years was 66% and 84% for ctDNA positive vs. ctDNA negative. |
Khakoo et al. (2020) | 47 | age 59 61.7% male 89% stage III | Baseline, during CRT, before and after surgery | ddPCR | 26.4 months (range 19.7–31.3) for MFS | There was no significant difference in response as evaluated by RECIST in patients with detectable ctDNA vs. undetectable at any time point. Poor responders were more likely to have detectable ctDNA after completion of CRT (p = 0.03). There was no association between baseline ctDNA status and MFS. MFS was shorter in patients with detectable ctDNA after CRT compared to patients with undetectable ctDNA (HR 7.1 95% CI 2.4–21.5, p < 0.001). Persistent ctDNA throughout treatment was associated with worse MFS (HR 11.5 95% CI 3.3–40.4, p < 0.001). |
Ji et al. (2020) | 46 | age 58 63% male NA | Baseline, before and after surgery | NGS | NA | No evaluation of an association between ctDNA status and treatment response. There was no significant correlation between ctDNA status at baseline, after CRT or after surgery and tumor recurrence or OS. Patients with low levels of bTMB at baseline had an increased risk of recurrence (p = 0.036) while patients with high levels after surgery had a high risk of recurrence (p = 0.026). |
Tie et al. (2019) | 159 | age 62 67% male 78% stage II | Baseline, before and after surgery | PCR | 24 months (range 1–55) for RFS | ctDNA levels at baseline and after CRT were not associated with pCR. High levels of postoperative ctDNA were associated with ypT3-4 and ypN1-2. There was no difference in RFS between ctDNA positive and ctDNA negative (HR 1.1 95% CI 0.42–3.0) at baseline. Three-year RFS was 50% and 85% for the ctDNA positive and ctDNA negative, respectively (after CRT), and 33% and 87% in the postoperative ctDNA positive and ctDNA negative groups. In regression analysis, ctDNA status remained the strongest independent predictor of RFS (HR 6.0 95% CI 2.2–16, p < 0.001). |
Pazdirek et al. (2020) | 33 | age 64 75% male 78% stage III | Baseline and during CRT | DCE | NA | No evaluation of an association between ctDNA status and treatment response. The overall probability of three-year survival was 91.2% in the ctDNA-negative and 71.4% in ctDNA-positive group (7/33 were positive for ctDNA). Positivity for ctDNA at baseline was associated with a significantly shorter DFS (p = 0.015) and OS (p = 0.010). |
Zhou et al. (2021) | 104 | age 60 64.4% male 77% stage III | Baseline, during CRT, before and after surgery | NGS | 18.8 months (range 3.1–21.3) for MFS | There was no association between ctDNA at baseline or during CRT and parameters that reflect tumor response (p > 0.05). Positive ctDNA at baseline, during and after CRT, and after surgery was associated with shorter period of time to distant metastasis. HR increased over each time point. Regression analyses showed that only median VAF of mutations at baseline remained an independent predictor of MFS compared to other pretreatment variables (HR 1.27 p < 0.001). |
Murahashi et al. (2020) | 85 | age 60 76.5% male 68% stage III | Baseline, before and after surgery | NGS | NA | There was no association between ctDNA status at baseline, after CRT, or after surgery and treatment response (pCR or cCR in patients treated with organ preservation). However change in MAF was associated with response to treatment (OR 7.4 95% CI 1.2–144, p = 0.0276). Increased RFS was observed in patients with ctDNA <0.5% vs. >0.5% (HR 17.1 95% CI 1–282, p < 0.000). |
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Dizdarevic, E.; Hansen, T.F.; Jakobsen, A. The Prognostic Importance of ctDNA in Rectal Cancer: A Critical Reappraisal. Cancers 2022, 14, 2252. https://doi.org/10.3390/cancers14092252
Dizdarevic E, Hansen TF, Jakobsen A. The Prognostic Importance of ctDNA in Rectal Cancer: A Critical Reappraisal. Cancers. 2022; 14(9):2252. https://doi.org/10.3390/cancers14092252
Chicago/Turabian StyleDizdarevic, Edina, Torben Frøstrup Hansen, and Anders Jakobsen. 2022. "The Prognostic Importance of ctDNA in Rectal Cancer: A Critical Reappraisal" Cancers 14, no. 9: 2252. https://doi.org/10.3390/cancers14092252